Role of Interleukin 6 (IL-6) in the detection of sepsis

          The levels of IL-6 (days 1, 2, 4, 6, 8, and 11), along with the other cytokines, have been shown to significantly increase compared to the controls, with its peak occurring on day 1, after which its levels gradually decline. In a 2018 study, it was stated that the levels of certain cytokines found as a result of endothelial injury were significantly elevated in the initial acute phase (day 1) in patients with sepsis than the control group. These include IL-1β, IL-6, IL-8, MCP-1, and PAI-1.[7]

          Endothelial injury is greatly linked to the development of sepsis. This injury can proliferate the generation of cytokines, including IL-6, IL-8, and MCP-1. This points out that there may be a role of endothelial cell injury in the formation of the cytokine network consisting of IL-6, IL-8, and MCP-1 for the duration of the acute phase of sepsis. Additionally, the increase in IL-6, IL-8, and MCP-1 could initiate a positive feedback system by augmenting endothelial cells’ inflammatory response.[8]

          Out of these cytokines, the level of IL-6 had been elevated most significantly during the acute phase. The striking concentration of IL-6 binds to the soluble form of the IL-6 receptor (IL-6R). This leads to the formation of the IL-6/IL-6R complex, which in turn pools with the cellular signal-transducing component – glycoprotein 130, including endothelial cells. As a result, IL-6 signal activation is elicited. Due to this process, endothelial injury is accelerated, leading to the accumulative generation of IL-6, IL-8, and MCP-1.[9]

          In a prospective controlled study of 2019, it was reported that among the patients with septic shock at presentation, the preliminary levels of IL-6 within six hours of clinical diagnosis were 444.3 pg/mL in the recovered survivors and 7609.5 pg/mL in non-survivors (P = 0.05). The follow-up IL-6 levels in survivors and non-survivors within 24 hours after discharge were 21.5 and 9976.5 pg/mL, respectively (P < 0.001). These findings showed that the IL-6 and PTX3 significantly declined in the patients who recovered and survived (P < 0.001). The levels remained tall and even substantially elevated in the non-survivors (P = 0.03 and P = 0.009, respectively).

          Some studies had shown that the diagnostic value of IL-6 was less than or equal to other specific cytokines. However, this study reported that serum levels of IL-6 and PTX3 were useful in identifying sepsis severity with optimum cut-off values. Furthermore, IL-6 is demonstrated to have greater diagnostic and prognostic value in comparison with PTX3, PCT, and CRP. IL-6 had been an independent risk factor for a 28-day death rate in people suffering from sepsis and septic shock.[10]

          Essentially, a decline in IL-6 levels was linked with an improved prognosis and superior recovery. Hence, its levels were considered to be the key predictor for clinical severity and fatal outcome.

Role of Tumor Necrosis Factor Alpha (TNF-Α) in the detection of sepsis

          TNF-α is acknowledged as a vital pro-inflammatory cytokine that plays a role in producing cytokines such as IL-6, IL-8, and MCP-1 along with IL-1β.9 However, the effects of TNF-α were not associated with the cytokines it gives rise to. This denotes the fact that TNF-α’s effect as a pro-inflammatory cytokine is partial or limited.

          It was similarly seen that the pathogen infection response increased the pro-inflammatory cytokines including IL-6, IL-8, IL-18 as well as tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokine (IL-10) in patients suffering from sepsis. However, the differences in the levels of TNF-α and certain other cytokines (IFN-α, IFN-γ, IL-12/IL-23p40, IL-17A, and IL-4) were not significant between the patients with sepsis and the controls.

          Subsequently, high levels of serum IL-10 and TNF-alpha and an elevated IL-10 to TNF-alpha ratio were found to be connected with mortality, while increased levels of TNF-alpha, IL-6, among others, were identified in those patients having early hemodynamic deterioration.[10]

          Another study conducted serial estimation of IL-6 and TNF-α in patients with sepsis. It was reported that the IL-6 levels declined from day 1 to 7 after admission in the survivor group. Also, the TNF-α level was substantially low on day 1 in the non-surviving female group.

          Henceforth, the findings suggested that a descending trend in IL-6 levels was associated with better sepsis prognosis.[11]

Conclusion

          The diagnostic procedure of sepsis has evolved with time and requires biomarkers that reflect infection, immune dysregulation, and organ dysfunction. The manifestation of biomarkers associated with the diagnosis or prognosis of sepsis can be supportive for clinicians and can improve patient care and the likelihood of survival.

          Thus, the inflammatory cytokines circulating in serum have been recognized as mediators of impairment in sepsis patients.[12] Numerous studies have shown the upregulation of the inflammatory cytokines, including TNF-α and IL-6 in septic conditions as compared to the healthy individuals.

          Subsequently, the systemic inflammatory response syndrome is considered to be linked with the progression of sepsis.[13] Hence, identification of inflammatory markers is taken as a means to estimate the prognosis of sepsis.